rs760351849

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM4PP5

The NM_001374675.1(HSF4):c.426_443dupGGTGCAGGCTTTGCGGGG(p.Gly148_Val149insValGlnAlaLeuArgGly) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,474,414 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000076 ( 1 hom. )

Consequence

HSF4
NM_001374675.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 0.507

Publications

0 publications found

Variant links:

Genes affected

HSF4 (HGNC:5227): (heat shock transcription factor 4) Heat-shock transcription factors (HSFs) activate heat-shock response genes under conditions of heat or other stresses. HSF4 lacks the carboxyl-terminal hydrophobic repeat which is shared among all vertebrate HSFs and has been suggested to be involved in the negative regulation of DNA binding activity. Two alternatively spliced transcripts encoding distinct isoforms and possessing different transcriptional activity have been described. [provided by RefSeq, Jul 2008]

HSF4 Gene-Disease associations (from GenCC):

cataract 5 multiple types
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
early-onset lamellar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
total early-onset cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HSF4 links:

ENSG00000265690 (HGNC:):

ENSG00000265690 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001374675.1.

PP5

Variant 16-67166010-A-AGGTGCAGGCTTTGCGGGG is Pathogenic according to our data. Variant chr16-67166010-A-AGGTGCAGGCTTTGCGGGG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522680.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HSF4	NM_001374675.1 link	c.426_443dupGGTGCAGGCTTTGCGGGG	p.Gly148_Val149insValGlnAlaLeuArgGly	disruptive_inframe_insertion	Exon 4 of 13	ENST00000521374.6	NP_001361604.1
HSF4	NM_001040667.3 link	c.426_443dupGGTGCAGGCTTTGCGGGG	p.Gly148_Val149insValGlnAlaLeuArgGly	disruptive_inframe_insertion	Exon 6 of 15		NP_001035757.1
HSF4	NM_001374674.1 link	c.426_443dupGGTGCAGGCTTTGCGGGG	p.Gly148_Val149insValGlnAlaLeuArgGly	disruptive_inframe_insertion	Exon 4 of 13		NP_001361603.1
HSF4	NM_001538.4 link	c.426_443dupGGTGCAGGCTTTGCGGGG	p.Gly148_Val149insValGlnAlaLeuArgGly	disruptive_inframe_insertion	Exon 6 of 15		NP_001529.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSF4	ENST00000521374.6 link	c.426_443dupGGTGCAGGCTTTGCGGGG	p.Gly148_Val149insValGlnAlaLeuArgGly	disruptive_inframe_insertion	Exon 4 of 13	1	NM_001374675.1	ENSP00000430947.2
ENSG00000265690	ENST00000580114.5 link	n.1053_1054insGGTGCAGGCTTTGCGGGG		downstream_gene_variant		5		ENSP00000464271.1

Frequencies

GnomAD3 genomes

AF:

0.0000351

AC:

AN:

142618

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000528

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000453

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

135488

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000758

AC:

101

AN:

1331796

Hom.:

Cov.:

AF XY:

0.0000898

AC XY:

AN XY:

656806

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30096

American (AMR)

AF:

0.00

AC:

AN:

34222

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23114

East Asian (EAS)

AF:

0.00

AC:

AN:

31890

South Asian (SAS)

AF:

0.0000757

AC:

AN:

79254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29088

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4296

European-Non Finnish (NFE)

AF:

0.0000899

AC:

AN:

1045678

Other (OTH)

AF:

0.0000185

AC:

AN:

54158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000351

AC:

AN:

142618

Hom.:

Cov.:

AF XY:

0.0000435

AC XY:

AN XY:

68992

show subpopulations

African (AFR)

AF:

0.0000528

AC:

AN:

37882

American (AMR)

AF:

0.00

AC:

AN:

14116

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3414

East Asian (EAS)

AF:

0.00

AC:

AN:

4644

South Asian (SAS)

AF:

0.00

AC:

AN:

4398

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8798

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.0000453

AC:

AN:

66204

Other (OTH)

AF:

0.00

AC:

AN:

1968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Mar 08, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-frame insertion of 6 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge

Cataract 5 multiple types

Uncertain:1

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HSF4-related disorder

Uncertain:1

Oct 13, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HSF4 c.426_443dup18 variant is predicted to result in an in-frame duplication (p.Ala145_Gln150dup). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-67199913-A-AGGTGCAGGCTTTGCGGGG). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.51

Mutation Taster

=41/59

disease causing

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over